National Institute of Mental Health (NIMH) scientists have linked a gene
variant that reduces dopamine activity in the prefrontal cortex to poorer
performance and inefficient functioning of that brain region during working
memory tasks, and to slightly increased risk for schizophrenia.

The finding, which must still be confirmed by independent teams of investigators,
emerged from an ongoing study of people with schizophrenia and their siblings.
The study is among the first to suggest a mechanism by which a gene might
confer susceptibility to a mental illness, say the researchers. Daniel
Weinberger, M.D., Michael Egan, M.D., NIMH Clinical Brain Disorders Branch,
and colleagues, report on their results in the May 29, 2001 Proceedings
of the National Academy of Sciences.

The most disabling form of mental illness, schizophrenia affects one
percent of the adult population, typically in young adulthood, with hallucinations,
delusions, social withdrawal, flattened emotions and loss of social and
personal care skills. Although its cause remains a mystery, evidence suggests
that it is at least 80% heritable, stemming from complex interactions
among several genes and non-genetic influences. Several chromosomal regions
have been implicated, but none have been definitely confirmed and no genes
have yet been linked to the disorder.

Given the syndrome's daunting complexity, Weinberger and colleagues have
been studying many traits to identify those that patients share with their
well siblings, hoping to turn up clues to susceptibility genes. Their
brain imaging studies had revealed that both well siblings and patients
falter on tasks of working memory and show abnormal activation of the
prefrontal cortex, which is required for such "executive" functions.
Studies have shown that the chemical messenger dopamine plays a pivotal
role in tuning the activity of the prefrontal cortex during such tasks.

A gene called COMT (catecho-o-methytransferase) had long been suspected
of being involved because it codes for an enzyme that breaks down dopamine
after it is secreted into the synapse. People inherit two copies of COMT
(one from each parent), each in either of two forms. The most common variant,
val, reduces prefrontal dopamine activity, while a somewhat less common
form, met, increases it.

Weinberger and colleagues administered a working memory task known to
activate the pre-frontal cortex, the Wisconsin Card Sorting Test (WCST),
to 181 schizophrenia patients, 219 of their well siblings and 75 normal
controls. They found that those who had inherited 2 copies of val, on
average, performed worse than those with only one copy. Those with two
copies of met performed best. COMT accounted for 4.1% of the variance
in test performance among patients and controls, suggesting that it influences
prefrontal functioning

When healthy siblings were asked to perform another working memory task
(N-back) while undergoing functional magnetic resonance imaging (fMRI),
the prefrontal brain activity of those with two copies of val was least
efficient; there was excessive activity for a given level of performance.

"It's as if they get poorer gas mileage out of their prefrontal
cortex if they have this genetic background," said Weinberger, who
led the research team. Brain activity of those with one copy of each variant
was more efficient, while activity of siblings who inherited two copies
of met showed the highest brain efficiency, on average.

Among 104 pairs of parents studied, the investigators discovered that
the val form of COMT was transmitted to offspring who eventually developed
schizophrenia more often than would be expected by chance: 75 times for
val, compared to 51 times for met. Inheriting two copies of the val form
accounts for a 1.5-fold increased risk for schizophrenia in the general
population.

The researchers suspect that COMT's effect, while modest, may be amplified
through interaction with other susceptibility genes and environmental
factors. For example, they are studying a gene in the brain's hippocampus
that, together with COMT, could boost schizophrenia risk three-fold.

Although it's not yet known exactly how the COMT val variant impairs
prefrontal efficiency, evidence suggests that by reducing dopamine it
reduces signal-to-noise ratios of communications between neurons, much
like static drowns out weak radio stations.

"The COMT val allele is certainly not a necessary or sufficient
causative factor for schizophrenia, nor is it likely to increase risk
only for schizophrenia," caution the researchers. "However,
its biological effect on prefrontal function and the relevance of prefrontal
function for schizophrenia implicate a mechanism by which it increases
liability for the disorder."

The researchers are planning to study a COMT inhibitor medication as
a possible adjunct treatment to enhance cognitive performance in patients
with the val variant. There is evidence that current anti-psychotic drugs
work by blocking D2 dopamine receptors in lower dopamine circuits. The
NIMH researchers propose that the COMT inhibitor will specifically enhance
dopamine circuits specific to the prefrontal cortex.

The National Institute of Mental Health (NIMH) is part of the National
Institutes of Health (NIH), the Federal Government's primary agency for
biomedical and behavioral research. NIH is a component of the U.S. Department
of Health and Human Services.